Transfer and Capture of Envelope Protein Receptor-Binding Domains in the Retroviruses

Abstract

The surface subunit (SU) of the envelope protein (Env) or retroviruses is highly variable due to adaptation to different hosts during their long evolutionary history. Several exogenous and endogenous retroviral gamma-like Env have a receptor-binding domain (RBD) in the amino-terminal region of SU that folds independently from the carboxyterminal SU C-domain. Two structurally distinct RBD classes have been described, one that adopts a modified immunoglobulin (Ig)-like domain fold and a second, in the Env of RDR interference group retroviruses, with a distinct {beta}-sheet fold. Here, the distribution of different RBD classes among exogenous and endogenous gammatype Env was determined by phylogenetic analyses of Env and structural modeling of retroviral SU with AlphaFold2. The patterns of RBD distribution indicate multiple RBD transfer events in the retroviruses. In addition, SU structural modeling identified an endogenous alpharetroviral-like Env in mammalian species with an amino-terminal RBD. This RDB has a typical IgV domain fold closely related both structurally and in sequence to the mammalian signal regulatory proteins (SIRP) , {beta} and {gamma}, indicating, for the first time, acquisition of an RBD from a mammalian gene by the retroviruses. The results described herein indicate intragenic env recombination between retroviruses and between retroviruses and their hosts as a major factor in the evolution of retroviral Env.